The document discusses several studies evaluating the use of rivaroxaban for various cardiovascular indications: - The COMPASS trial found that dual antiplatelet therapy with rivaroxaban and aspirin reduced cardiovascular events compared to aspirin alone in patients with coronary artery disease, including those with prior percutaneous coronary intervention. - A sub-analysis of COMPASS showed consistent reductions in cardiovascular outcomes with dual antiplatelet therapy regardless of the timing of prior PCI. Increased major bleeding was also observed. - The RIVER trial aimed to evaluate rivaroxaban versus warfarin for stroke prevention in atrial fibrillation patients with bioprosthetic mitral valves through a randomized, open-label, noninferior

1. Expanding Roll of RIVAROXABAN
THE EXPERT DIAGONOSIS TALK
(TED TALK)

2. Emerging Role of DOACS (RIVAROXABAN)

3. Belch et al. journal of vascular surgery. 2010
Dutch bypass Oral anticoagulants or Aspirin (BOA) study Group.Lancet.2000

4. Objective
In PAD patients undergoing lower extremity revascularization for
ischemic symptoms:

5. Capell WH, Bonaca MP, Nehler MR…Hiatt WR AHJ 2018

6. ARR – absolute risk reduction, NNT number needed to treat
Months from Randomization

8. RIVAROXABAN in CAD

20. Rivaroxaban plus aspirin versus with aspirin in
patients with prior percutaneous coronary
Intervention (PCI): Insights from the COMPASS
Trial
Kevin R. Bainey1, Scott D. Berkowitz2, Deepak L. Bhatt3, John W. Eikelboom4, Keith A. Fox5, Basil S. Lewis6, TamaraMarsden7, Eva Muehlhofer8, Dragos
Vinereanu9, Petr Widimsky10, Robert C. Welsh1
1Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada; 2Bayer U.S., LLC, Whippany, NJ, USA; 3Brigham and Women’s Hospital
Heart and Vascular Center and Harvard Medical School Boston, MA, USA; 4McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada;
5Department of Medicine, University of Edinburgh, Edinburgh, UK; 6Lady Davis Carmel Medical Center, Haifa, Israel;
7Population Health Research Institute, Hamilton, ON, Canada; 8Bayer AG, Wuppertal, Germany; 9University
of Medicine and Pharmacy Carol Davila, Bucharest, Romania;10Charles University, Prague, Czech Republic
American Heart Association Scientific Sessions 2019
Clinical Trial Registration: NCT01776424

21. Background
• The COMPASS trial demonstrated dual pathway inhibition (DPI) with rivaroxaban
2.5 mg twice-daily plus aspirin 100 mg once-daily versus aspirin 100 mg once- daily reduced the primary
MACE outcome of cardiovascular death, MI, or stroke as well as mortality in patients with chronic coronary
syndromes or peripheral artery disease.
• Patients undergoing PCI are routinely treated with DAPT
• However, the efficacy of DPI with prior PCI is less well studied
DAPT=dual antiplatelet therapy; MACE=major adverse cardiac event; MI=myocardial infarction; PCI=percutaneous coronary intervention

22. Objectives
• In a pre-specified sub-group analysis from COMPASS, we examined
the impact of dual pathway inhibition compared to aspirin alone in
chronic coronary syndrome patients with or without prior PCI.
• Among patients with a prior PCI, we studied the effects of treatment
according to the timing of prior PCI.
PCI=percutaneous coronary intervention

23. Study Flow
COMPASS PCI
16, 560 chronic coronary syndrome patients
No Prior PCI
(n=6698, 40.4%)
Prior PCI
(n=9862, 59.6%)
DPI
(n=4963, 50.3%)
Aspirin
(n=4899, 49.7%)
DPI
(n=3342, 49.9%)
Aspirin
(n=3356, 50.1%)

24. Baseline Characteristics
Prior PCI
(n=9862)
No Prior PCI
(n=6698)
Age, years 68·2 (7·8) 68·5 (7·9)
Female sex 1918 (19·4%) 1461 (21·8%)
Risk factors
Cholesterol, mmol/L 4·1 (1·0) 4·2 (1·1)
Tobacco use 2082 (21·1%) 1281 (19·1%)
Hypertension 7352 (74·5%) 5133 (76·6%)
Peripheral arterial disease 1731 (17·6%) 1563 (23·3%)
Diabetes 3516 (35·7%) 2558 (38·2%)
Previous MI 7372 (74·8%) 3993 (59·6%)
Previous stroke 267 (2·7%) 280 (4·2%)
Medication
ACE inhibitor or ARB 7266 (73·7%) 4636 (69·2%)
Beta-blocker 7304 (74·1%) 4964 (74·1%)
Lipid-lowering agent 9250 (93·8%) 5977 (89·2%)
Data are mean (SD) or n (%). eGFR=estimated glomerular filtration rate. MI=myocardial infarction. ACE inhibitor=angiotensin-converting enzyme inhibitor. ARB=angiotensin
receptor blocker

25. Prior PCI characteristics according to
treatment received
PCI Occurrence
Low-dose rivaroxaban
plus aspirin
(n=4963)
Aspirin alone
(n=4899)
Timing of prior PCI
Less than one year prior to randomization 249 (5·0%) 231 (4·7%)
1 year to <2 years prior to randomization 1008 (20·3%) 897 (18·3%)
2 years to <3 years prior to randomization 616 (12·4%) 663 (13·5%)
3 years or more prior to randomization 3089 (62·2%) 3105 (63·4%)
PCI type
Single-vessel PCI 3016 (60·8%) 3071 (62·7%)
Multi-vessel PCI 1947 (39·2%) 1828 (37·3%)
Data are n (%). PCI=percutaneous coronary intervention.

26. Primary Efficacy Endpoint CV death, MI
or stroke (ITT)
Prior PCI Interaction p=0.85 No Prior PCI
HR 0.74
(95% CI 0.61-0.88)
HR 0.76
(95% CI 0.61-0.94)

27. Secondary Efficacy Endpoint All-Cause
Death (ITT)
Prior PCI No Prior PCI
HR 0.73
(95% CI 0.58-0.92)
HR 0.80
(95% CI 0.64-1.00)
Interaction p=0.59

28. Safety Endpoint Major Bleeding*
*The primary safety outcome was modified International Society of Thrombosis and Hemostasis (ISTH) major bleeding, defined as: i) fatal bleeding
and/or ii) symptomatic bleeding in a critical area or organ or bleeding into the surgical site requiring re-operation and/or iii) bleeding leading to
hospitalization (including presentation to an acute care facility without an overnight stay).
Symptomatic bleeding into a critical organ or area included intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or
0 1y 2y 3y 0 1y 2y 3y
Follow-up Time Follow-up Time
Cumulative
Incidence
Risk
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
DPI
ASA Alone
# at Risk
0
4963
4899
1
4346
4319
2
2216
2298
3
406 DPI
427 ASA Alone
Major Bleed, Previous PCI
Cumulative
Incidence
Risk
0.0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
DPI
ASA Alone
# at Risk
0
3342
3356
1
2839
2859
2
1412
1392
3
221 DPI
226 ASA Alone
Major Bleed, No PCI
Prior PCI No Prior PCI
Interaction p=0.68
HR 1.72
(95% CI 1.34-2.21)
HR 1.58
(95% CI 1.15-2.17)

29. Other Bleeding Endpoints
Low-doserivaroxaban
plus aspirin
(n=8305)
Aspirin
alone
(n=8255)
Low-dose rivaroxaban plus aspirin vs·
aspirin alone
Event Subgroup
Subgroup
n
Patients with
events (%)
Subgroup
n
Patients with
events (%)
HR
(95% CI)
P value for
interaction
Major Bleed Prior PCI 4963 165 (3·3%) 4899 96 (2·0%) 1·72 (1·34-2·21) 0·68
Major Bleed No prior PCI 3342 98 (2·9%) 3356 62 (1·8%) 1·58 (1·15-2·17) ·
Minor Bleed Prior PCI 4963 489 (9·9%) 4899 291 (5·9%) 1·71 (1·48-1·98) 0·74
Minor Bleed No prior PCI 3342 284 (8·5%) 3356 162 (4·8%) 1·78 (1·47-2·16) ·
Fatal Bleed Prior PCI 4963 7 (0·1%) 4899 2 (<0.1%) 3·47 (0·72-16·7) 0·15
Fatal Bleed No prior PCI 3342 7 (0·2%) 3356 8 (0·2%) 0·87 (0·32-2·41) ·
ICH Bleed Prior PCI 4963 17 (0·3%) 4899 13 (0·3%) 1·30 (0·63-2·68) 0·52
ICH Bleed No prior PCI 3342 9 (0·3%) 3356 10 (0·3%) 0·89 (0·36-2·20) ·
Data are n (%) or HR (95% CI). HR=hazard ratio. PCI=percutaneous coronary intervention. ICH=intracranial hemorrhage

30. Benefit of DPI vs Aspirin
as a function of time from the most recent percutaneous coronary intervention
CV Death, MI, Stroke All-cause mortality
The p-value of interaction between treatment group and time since percutaneous
coronary intervention was 0.66
The p-value of interaction between treatment group and time since percutaneous
coronary intervention was greater than 0.99

31. Conclusions
• DPI compared with aspirin alone:
• Produced consistent reductions in CV death, MI, stroke as well as all-cause death with or without prior
PCI
• Increased major bleeding without a significant increase in fatal bleeding or intracranial hemorrhage
• In patients with prior PCI:
• Consistent reductions in CV death, MI, stroke as well as all-cause death were demonstrated with DPI
irrespective of the timing of prior PCI (as far back as 10-years)

32. Rivaroxaban Versus Warfarin In Patients With Atrial
Fibrillation and Bioprosthetic Mitral Valves:
The RIVER Randomized Trial

33. Background and Rationale
 Patients with atrial fibrillation and a bioprosthetic mitral valve require long-
term anticoagulation, but the optimal therapeutic strategy remains
uncertain.
 The efficacy and safety of DOACs in patients with atrial fibrillation and a
mitral bioprosthetic valve are based on subgroup analyses of pivotal trials.
ARISTOTLE (apixaban) N = 31 patients
ENGAGE-TIMI 48 (edoxaban) N = 131 patients
 Patients with bioprosthetic valves were excluded from the ROCKET-AF trial.

34. Rivaroxaban Warfarin
Primary Endpoint*: death, major CV events**, or major bleeding
INR target
(2.0-3.0 inclusive)
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Patients with atrial fibrillation or flutter and a bioprosthetic mitral valve
Randomized
(Concealed)
Open-label
Study Design
ITT ITT
Follow-up 12 months
* adjudicated by a blinded Clinical Events Classification Committee
** stroke, TIA, valve thrombosis, systemic embolism not related to the central nervous system, or
hospitalization for heart failure.
Noninferiority RCT

35. Rivaroxaban Warfarin
Primary Endpoint*: death, major CV events**, or major bleeding
INR target
(2.0-3.0 inclusive)
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Patients with atrial fibrillation or flutter and a bioprosthetic mitral valve
Randomized
(Concealed)
Open-label
Study Design
ITT ITT
Follow-up 12 months
* adjudicated by a blinded Clinical Events Classification Committee
** stroke, TIA, valve thrombosis, systemic embolism not related to the central nervous system, or
hospitalization for heart failure.
Noninferiority RCT

36.  Efficacy
– Composite outcome of CV death or thromboembolic events (stroke, TIA,
valve thrombosis, venous thromboembolism, or non-CNS systemic
embolism)
– Individual components of the combined endpoints
 Safety
– Bleeding events (major, minor, minimal, or fatal)
– Bleeding events are classified based on the ROCKET-AF definition, but also
using the TIMI and BARC criteria
Secondary Endpoints
All endpoints were adjudicated by a blinded Clinical Events Classification Committee

37.  Primary Endpoint Analysis
– Restricted Mean Survival Time (RMST)*:
 Sample Size
– Noninferiority margin: between-group difference of - 8 days in the RMST (approximately 2% of
365 days). N =1000 patients
– 80% power, event rate of 14.5% in the warfarin group, with a hazard ratio of 0.79 and an alpha
level of 5%.
Statistical Analysis
the mean time free from
an outcome event up to
365 days, reflecting the
area under the survival
curve
RMST difference (days)
95% CIs
* not dependent on the number of
events and on the assumption of
proportional hazards
rivaroxaban minus
warfarin, so negative
values indicate an
increased risk from
rivaroxaban treatment
RMST

38. Randomized to
Rivaroxan
N = 500
Randomized to
Warfarin
N=505
Study Drug
Discontinuation 52 (10.4%) 36 (7.1%)
Lost to
Follow-up
0 (0.0%) 6 (0.3%)
Withdrawal of
Consent
0 (0.0%) 0 (0.0%)
1005 patients randomized
CONSORT Diagram
Median TTR*
65.5%
(IQR 51.3 to 70.5)
* method of Rosendaal et al.

39. Rivaroxaban
(N=500)
Warfarin
(N=505)
Age (y), mean ± SD 59.4 ±12.4 59.3 ± 11.8
Female sex (%) 62.2 58.6
Congestive Heart Failure (%) 40.4 37.2
Hypertension (%) 61.6 59.8
Diabetes Mellitus (%) 14.8 12.7
Prior Stroke/TIA (%) 15.0 15.3
Prior CAD (%) 21.2 19.1
CHA2DS2-VASc Score, mean ± SD 2.7 ± 1.5 2.5 ± 1.3
Atrial fibrillation (%) 96.0 95.3
Flutter (%) 4.0 4.7
Baseline Characteristics

40. Rivaroxaban
(N=500)
Warfarin
(N=505)
Time from Mitral Valve Implantation
Up to 3 months (%)
≥ 3 months and < 1 year (%)
≥ 1 years and < 5 years (%)
≥ 5 years and < 10 years (%)
Unknown (%)
18.8
18.2
32.0
29.6
1.4
18.8
15.4
32.4
31.6
1.5
Time from Mitral Valve Surgery to Randomization

41. Primary Endpoint
0
2
4
6
8
10
12
14
16
18
20
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (Days)
Death,
Major
CV
Events,
or
Major
Bleeding
(%)
Warfarin Rivaroxaban
500 493 491 484 483 481 479 473 469 466 459 453 340
505 496 487 483 474 469 463 458 456 455 450 445 346
Warfarin
Rivaroxaban
Patients at risk
At the end of the 1-year follow-up period, event-free survival time was
7.4 days longer with rivaroxaban compared with warfarin

42. Primary Endpoint
0
2
4
6
8
10
12
14
16
18
20
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (Days)
Death,
Major
CV
Events,
or
Major
Bleeding
(%)
Warfarin Rivaroxaban
500 493 491 484 483 481 479 473 469 466 459 453 340
505 496 487 483 474 469 463 458 456 455 450 445 346
Warfarin
Rivaroxaban
Patients at risk
RMST Difference (days) 7.4 (95% CI -1.4 to 16.3)
Non-inferiority margin = - 8 days
P for non-inferiority <0.001
* negative values indicate an increased risk from
rivaroxaban treatment.

43. RMST Difference, days
(95% CI) P value
Analysis Rivaroxaban - Warfarin Noninferiority Superiority
ITT 7.4 (-1.4 to 6.3) <0.001 0.10
Per-protocol 9.6 (2.2 to 16.9) <0.001 0.01
As-treated 10.5 (1.9 to 19.1) <0.001 0.01
Primary Endpoint
Primary Endpoint: death, major CV events, or major bleeding
RMST: restricted mean survival time

44. Endpoint
Rivaroxaban
(N=500)
Warfarin
(N=505)
HR
(95% CI)
P value
CV mortality or thromboembolic
events (%)
3.4 5.1 0.65 (0.35 to 1.20) 0.17
Total Stroke (%) 0.6 2.4 0.25 (0.07 to 0.88) 0.03
CV Death (%) 2.2 2.6 0.85 (0.38 to1.90) 0.69
All-cause Death (%) 4.0 4.0 1.01 (0.54 to 1.87) 0.98
Valve thrombosis (%) 1.0 0.6 1.68 (0.40 to 7.01) 0.48
Non-CNS embolism (%) 0.0 0.2 - -
Secondary Efficacy Endpoints

45. Endpoint
Rivaroxaban
(N=500)
Warfarin
(N=505)
HR
(95% CI)
P
value
Major (%) 1.4 2.6 0.54 (0.21 to1.35) 0.18
Intracranial bleeding (%) 0.0 1.0 - -
Fatal bleeding (%) 0.0 0.4 - -
Clinically Relevant non major (%) 4.8 4.6 1.05 (0.60 to1.87) 0.85
Minor (%) 7.4 9.7 0.75 (0.49 to1.15) 0.18
Total (%) 13.0 15.4 0.83 (0.59 to1.15) 0.25
Bleeding Events
Bleeding events defined by the ROCKET-AF trial criteria

46. 47/500 (9.4%)
28/321 (8.7%)
19/179 (10.6%)
20/189 (10.6%)
27/311 (8.7%)
41/425 (9.6%)
6/75 (8.0%)
6/94 (6.4%)
6/91 (6.6%)
7/160 (4.4%)
27/148 (18.2%)
33/361 (9.1%)
6/47 (12.8%)
347.5 [341.8 to 353.1]
349.0 [342.1 to 355.8]
344.8 [335.0 to 354.7]
345.2 [335.4 to 355.0]
348.9 [342.0 to 355.7]
346.7 [340.4 to 353.0]
352.2 [340.3 to 364.0]
348.6 [335.1 to 362.1]
351.3 [339.3 to 363.3]
356.2 [348.8 to 363.6]
336.3 [324.1 to 348.5]
346.8 [339.9 to 353.7]
334.8 [310.6 to 359.0]
52/505 (10.3%)
30/329 (9.1%)
22/176 (12.5%)
25/209 (12.0%)
27/296 (9.1%)
39/441 (8.8%)
13/64 (20.3%)
18/95 (18.9%)
4/78 (5.1%)
14/164 (8.5%)
16/160 (10.0%)
36/358 (10.1%)
10/60 (16.7%)
340.1 [333.2 to 346.9]
342.2 [334.0 to 350.5]
336.0 [323.8 to 348.3]
333.6 [321.6 to 345.6]
344.6 [336.6 to 352.6]
344.1 [337.4 to 350.8]
312.3 [284.6 to 339.9]
313.5 [290.6 to 336.3]
355.1 [344.6 to 365.6]
348.6 [339.4 to 357.7]
338.6 [326.2 to 351.1]
340.2 [332.0 to 348.5]
328.6 [306.0 to 351.2]
Age
Gender
Antiplatelet at baseline
Time from mitral valve implantation
CrCl (mL/mim)
All
< 65
≥ 65
Male
Female
No
Yes
< 3 months
≥ 3 months and < 1 year
≥ 1 year < 5 years
≥ 5 years
≥ 50
< 50
No./Total No.(%) No./Total No.(%)
RMST [95% CI] RMST [95% CI]
Rivaroxaban Warfarin
1 2 3
<-- Warfarin Better Rivaroxaban Better -->
Differences of RMST, days (Rivaroxaban - Warfarin)
-20 -15 -10 -5 0 5 10 15 20 25 30 35 40 45
Subgroup Analysis

47. Primary Endpoint
Time from mitral valve implantation < 3 months
RMST Difference (days) 35.2 (95% CI 8.6 to 61.7)
HR 0.31 (0.12 to 0.79); P Value = 0.01
0
4
8
12
16
20
24
28
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (Days)
(%)
Warfarin Rivaroxaban
94 92 92 90 90 90 90 89 89 88 87 87 69
95 89 85 84 84 83 81 79 78 78 76 74 64
Warfarin
Rivaroxaban
Patients at risk
Death,
Major
CV
Events,
or
Major
Bleeding
(%)

48. Conclusion
 In conclusion, in patients with atrial fibrillation and a
bioprosthetic mitral valve, rivaroxaban is noninferior to
warfarin with respect to mean time free from death, major
cardiovascular events, or major bleeding.
 Since rivaroxaban does not require monitoring and has a
more consistent anticoagulant effect, which is less
influenced by food or concomitant medications, it
represents an attractive alternative to warfarin for this
patient population.